Exome Sequencing Reveals a High Prevalence of BRCA1 and BRCA2 Founder Variants in a Diverse Population-Based Biobank

Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant positive individuals in the general population are unaware of their risk, and little is known about the prevalence of pathogenic BRCA1/2 variants in non-European populations. We investigated BRCA1/2 prevalence and impact using exome sequencing and electronic health record (EHR) data from 30,223 adult participants of the BioMe Biobank in New York City. There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. In sub-populations defined by genetic ancestry, the highest prevalence was in individuals of Ashkenazi Jewish (AJ; 1 in 49), Filipino and Southeast Asian (1 in 81), and Non-AJ European (1 in 103) descent. Among 218 variant positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 7 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 25 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar, or that had uncertain or conflicting evidence for pathogenicity. Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion African genetic ancestry and the likelihood of harboring a BRCA1/2 variant with uncertain or conflicting evidence for pathogenicity. Based on EHR and participant questionnaire data, ~28% of variant positive individuals had a personal history, and ~45% a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant positive individuals had evidence of prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (38%) than those with other pathogenic variants (19%). These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.